The term “retinoid” is commonly used to define vitamin A analogues that bind to nuclear retinoid receptors; retinoic acid receptors (RAR) and retinoid X receptors (RXR). Once the retinoid derivative is coupled to the receptors, the latter form homo- or heterodimers, and through binding to the response element (RARE or RXRE) upstream of the target gene, regulates the gene expression as a transcriptional factor influencing cellular differentiation, tissue morphogenesis and programmed cell death. As a consequence, retinoid derivatives are promising compounds to prevent and/or treat cancers of various organs.
WO03/011808 filed in the name of the Applicant, describes retinoid derivatives endowed with antiangiogenic, antitumoral and pro-apoptotic activities. ST1926 (adarotene, example 4 of the above application) belongs to a so-called class of atypical retinoids and was found to be a potent pro-apoptotic agent for the treatment of neoplastic diseases. More recently, the same Applicant filed an international application dealing with the combination between a retinoid derivative and a platinum anticancer agent (WO08/077772).
The Applicant also filed an application (WO07/071605) concerning the use of a 4-O-methyl analogue of adarotene (ST1898) for the preparation of a medicament for treating pathological states, which arise from a complex series of cellular responses to vascular injury.
Dawson M. I., et al., recently published a pharmacophore model related to 4-[3′-(1-adamantyl)-4′-hydroxyphenyl]-3-chlorocinnamic acid, based on QSAR analyses relating the polar termini with cancer cell growth inhibition (Dawson M. I., et al., J. Med. Chem., 2007, 50, 2622). A further study from the same authors reveals an important interaction between the H atom of the 4′-OH of the retinoid derivative and the side chain of the residue Phe-96 of the small heterodimer partner through hydrogen-II interaction thus stabilizing the complex (Dawson M I., et al., J. Med. Chem., 2008, 51, 5650).
In WO07/000383, the Applicant reported the cytotoxicity activity of retinoid derivatives against NCI H460 tumour cells. 4′-OH retinoid adduct (ST1926) showed an IC50 value a log unit lower than that of its 4′-OMe analogue (ST1898).
The same Applicant also reported the antiproliferative activity of, among others the above two compounds (ST1926 and its methylated analogue ST1898) on IGROV-1, IGROV-1/Pt1, and NB4 cellular lines (Cincinelli R., et al., Bioorg. Med. Chem., 2007, 15, 4863). Those results, as already demonstrated on different cell lines reveal that the 4′-OH retinoid compound is more active than its 4′-OMe counterpart.
It is well known to those skilled in the art that a major mechanism of elimination of drugs from the body stream occurs through glucuronidation favouring excretion by the urines. It has been reported that that retinoyl β-glucuronide is synthesized rapidly from orally administered all-trans retinoic acid and can be detected in the blood within 30 min after the administration of retinoic acid (Barua A B., et al., Biochem. J., 1991, 277, 527). It is also well known that phenol derivatives can be substrate of UDP-glucuronosyltransferases (Ethell T. B., et al., Drug Metab. and Depos., 2002, 30, 6, 734).
Despite the many efforts over the past decades aimed at finding new and more potent retinoid derivatives endowed with antiangiogenic, antitumoral and/or pro-apoptotic activities, there is still a strong medical need of more adequate medicaments.